In recent years, there has been a significant change in the way that chiral compounds are viewed within the pharmaceutical industry. In the past, many molecules containing asymmetric centres were launched onto the drug marketplace as racemic mixtures. Subsequent concerns as to the safety and/or efficacy of such racemic drugs have persuaded the industry to research and develop single stereoisomer drugs. These concerns were based on the concept that racemic drugs could be considered to be 50% impure, since one isomer of a given racemic mixture is often pharmacologically inactive or significantly less active than the other isomer; indeed, one isomer may exert a different action or give origin to unwanted side-effects. Isomeric compounds may undergo different metabolic processes which complicate pharmacokinetic issues further. Consequently, drug regulatory authorities have become increasingly more cautious and frequently demand concise information on the properties and behaviour of individual isomers.
A particularly interesting example in this respect is the case of oxcarbazepine (OXC), the 10-keto analogue of carbamazepine (CBZ).

These two compounds are structurally very similar and are currently used in the treatment of epilepsy. Oxcarbazepine was designed to avoid the oxidative metabolic transformation of CBZ and is claimed to be a better tolerated drug (Grant, S. M. et al., Drugs, 43, 873-888 (1992)). However oxcarbazepine undergoes rapid and complete metabolism in vivo to the racemic 10-hydroxy derivative of oxcarbazepine, called “MHD” (see (±)-MHD, Schutz, H. et al., Xenobiotica, 16(8), 769-778 (1986)) and therefore represents an apparently achiral drug which undergoes metabolic transformation to give a mixture of two pharmacologically active enantiomers.
The synthesis and improved anticonvulsant properties of (S)-(−)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide (eslicarbazepine acetate), and (R)-(+)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide (R-(+)-licarbazepine acetate), both single-isomer drugs specifically designed to avoid such formation of racemic mixtures of active metabolites have been described (Benes, J. et al., U.S. Pat. No. 5,753,646 and Benes, J. et al., J. Med. Chem., 42, 2582-2587 (1999)). The key step of the synthesis of compounds eslicarbazepine acetate and R-(+)-licarbazepine acetate involves the resolution of racemic 10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide ((±)-MHD) into its separate, optically pure stereoisomers, (S)-(+)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide ((S)-(+)-MHD), and (R)-(−)-10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide ((R)-(−)-MHD), which are the principal intermediates.
Both stereoisomers of MHD are known compounds and are commonly used as standards in studies of oxcarbazepine metabolism. Additionally, MHD is a sodium channel blocker, and has potential efficacy in the treatment of acute manic episodes of bipolar I disorders.
The resolution of the racemic alcohol, (±)-MHD, has been previously described in the chemical literature (Benes, J. et al., J. Med. Chem., 42, 2582-2587 (1999) and Volosov, A. et al., Epilepsia, 41(9), 1107-1111 (2000)). These methods involve the formation of diastereoisomeric menthoxyacetate-ester derivatives of (±)-MHD; by taking advantage of the different solubilities of these diastereoisomeric esters, separation is possible by fractional crystallisation and subsequent hydrolysis affords the individually pure stereoisomers, (S)-(+)-MHD and (R)-(−)-MHD. However, this method was utilised for the preparation of only rather small quantities of each stereoisomer and contains certain inherent disadvantages which preclude its use for the preparation of pilot-scale quantities and thereafter industrial production. The necessary optically pure resolving agents, (+) and (−)-menthoxyacetic acid are extremely expensive and are not readily available in sufficiently large quantities from commercial sources. Their preparation from cheaper, readily available optically pure (+) or (−)-menthol could be considered, but this preparation is tedious, slow and potentially dangerous. Furthermore, these menthoxyacetic acids require ‘activation’ in order to react with (±)-MHD and form the key intermediate diastereoisomeric menthoxyacetate esters. This activation is normally achieved via conversion of the free acids to the acid chlorides (these acid chlorides are again very expensive products from commercial sources), an extra synthetic step which requires the use of unpleasant halogenating reagents such as for example thionyl chloride or oxalyl chloride. Alternatively, this reaction can be accomplished using a coupling reagent such as for example dicyclohexylcarbodiimide. This reagent is also expensive; additionally it is difficult to manipulate due to its low melting point and is indicated as a potent skin irritant, thus posing health risks for workers. Often there are encountered difficulties in removing completely the dicyclohexylurea by-product from the wanted product. A further and very serious limitation of this method is the relatively low yield obtained of the optically pure menthoxyacetate ester which is isolated after crystallisation, in yields usually only marginally better than 20% (the maximum yield being 50% for each isomer).
WO02/092572 discloses a process for separating the stereoisomers of (S)-(+)-MHD and (R)-(−)-MHD from the racemic mixture by means of a process which involves the use of an appropriate tartaric acid anhydride to resolve the stereoisomers. In particular, the (2R,3R)-di-O,O′-substituted-tartartic acid anhydride can be used to precipitate the diastereoisomeric precursor of (S)-(+)-MHD, and the (2S,3S)-di-O,O′-substituted-tartartic acid anhydride can be used to precipitate the diastereoisomeric precursor of (R)-(−)-MHD. eslicarbazepine acetate and R-(+)-licarbazepine acetate may be obtained from the resolved (S)-(+)-MHD and (R)-(−)-MHD by acylation.
The dibenz/b,f/azepine derivatives of particular interest in the present invention are the compounds with the following chemical formula:
wherein R is alkyl, aminoalkyl, halogenalkyl, aralkyl, cycloalkyl, cycloalkylalkyl, alkoxy, phenyl or substituted phenyl or pyridyl group; the term alkyl means carbon chain, straight or branched, containing from 1 to 18 carbon atoms; the term halogen represents fluorine, chlorine, bromine or iodine; the term cycloalkyl represents a saturated alicyclic group with 3 to 6 carbon atoms; the term aryl represents unsubstituted phenyl group or phenyl substituted by alkoxy, halogen or nitro group. Compounds of formula IA and IB are disclosed in U.S. Pat. No. 5,753,646.